Cases of Lyme disease (LD), due to the spirochete, Borrelia burgdorferi (Bb), are increasing. Accurate laboratory tests are needed to establish or exclude an early diagnosis of Lyme disease and to monitor the efficacy of therapy. The overall objective of this proposal is to assess Bb specific immune complexes (IC) as a sensitive and specific marker for: early diagnosis, for active infection, and for the efficacy of therapy in Lyme disease. Specific Aims are to determine (1) whether antibody (Ab) to Bb in IC (with corresponding Bb antigen) is detectable earlier than free anti-Bb Ab, within a clinically useful time period; and (2) whether the response to therapy correlates with the relative quantity of complexed Bb Ab (i.e., more early in the infection, with less or none after eradication and recovery) using serial serum samples from individual patients. The rationale for this study is the general observation that in many infections complexed Ab, bound to its antigen (Ag) target, can be detected before free Ab. In addition, in contradistinction to free Ab, complexed Ab is likely to reflect active disease. Our data supports these concepts in Lyme disease. In addition to a huge frozen serum bank, we will longitudinally study IC and free Ab and Ag components, in serial serum samples, from patients (25-50 per year) who fulfill a rigid definition of Lyme disease and controls. We will use a practical and simple, polyethylene glycol, assay to isolate and dissociate the IC, as well as other assays, in conjunction with ELISA and Western blots. Results will be statistically analyzed to prove or disprove the hypotheses of the specific aims.